2005 : WHAT DO YOU BELIEVE IS TRUE EVEN THOUGH YOU CANNOT PROVE IT?

I believe that it is possible to change adult cells from one phenotype to another.

The birth of Dolly provided the insight behind this belief. She was the first adult cloned from another adult, of any species. Previously biologists had believed that the mechanisms that direct the formation of all of the different tissues that make up an adult were so complex and so rigidly fixed that they could not be reversed. Her birth demonstrated that the mechanisms that were active in the nucleus transferred from the mammary epithelial cell could be reversed by unknown factors in the recipient unfertilised egg.

We take for-granted the process by which the single cell embryo at fertilisation gives rise to all of the many tissues of an adult. As almost all of those cells have the same genetic information, the changes must be brought about by sequential differences in function of the genes. An impression is beginning to emerge of the factors that bring about these sequential changes, although much more remains to be learned. In particular, very little is known of the hierarchy of influence of the several regulatory factors.

I believe that a greater understanding of these mechanisms will allow us to cause cells from one tissue to form another different tissue. We have long been accustomed to the idea that cells are influenced by their external environment and use specific methods of tissue culture to control their function in the laboratory. The new research introduces an additional dimension. We will learn how to increase the activity of the intracellular factors to achieve our aims. This may be by direct introduction of the proteins, use of small molecule drugs to modulate expression of regulatory genes or transient expression of those key genes. We have much to learn about the optimal approach to „transdifferentiation¾. Is it necessary to reverse the process of differentiation to an early stage in the same pathway? Or is it possible to achieve change directly from one path to another? The answer may vary from one tissue to another.

The medical implications will be profound. Cells of specific tissues will be available from patients either for research to understand genetic differences or for their therapy, This is not to suggest that we cease research on embryo stem cells because knowledge from their use will be essential to develop the new approaches that I envisage. Conversely, understanding of the mechanisms of reprogramming cells will create important new opportunities in the use of embryo stem cells. As many options as possible should be available to the researcher and clinician.

It is my belief that, ultimately, this approach to tissue formation will be the greatest inheritance of the Dolly experiment. The ramifications are far wider than those that involve the production of cloned offspring.